Uche, Uzodinma
(2019)
PIK3IP1/TrIP restricts activation of T cells through inhibition of the PI3K/Akt Pathway.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Phosphatidylinositide-3-Kinases (PI3Ks) are a family of lipid kinases that play important intracellular signaling roles in cellular functions such as cell proliferation, motility, growth, intracellular trafficking, differentiation and survival. PI3K produces PIP3 which further facilitates the activation of downstream effectors such as Akt and PDK1. These effectors facilitate the cellular processes associated with PI3K activity. Conversely, because of the nature of PI3Ks roles, dysregulation of PI3K, leading to over-activity of the PI3K pathway is implicated in many cancers. PTEN, SHIP and INPP4B are negative regulators of PI3K activity that function downstream of PI3K and have been shown to act as tumor suppressors. Recently, PI3K Interacting Protein 1 (PIK3IP1) or TrIP (Transmembrane Inhibitor of PI3K), a novel negative regulator that functions upstream and proximal to PI3K, has been identified. TrIP, is a transmembrane protein and has been shown to down regulate PI3K activity leading to reduction of phosphorylation on Akt in carcinoma cell lines. Our lab was the first to show that TrIP can inhibit TCR signaling and TCR activation, in T cell lines. Here I have shown that both the extracellular kringle domain and intracellular p85-like domain are required for TrIP to inhibit PI3K and T cell activation. Interestingly, I have also found that cell surface expression of TrIP is acutely down-regulated during T cell activation. Furthermore, my results indicate that TrIP oligomerizes in order to inhibit PI3K signaling. Using knockout mice lacking expression of TrIP in T-cell compartments, I have been able to better define the requirements for TrIP in primary T cells upon TCR activation and in response to infection. Finally, I have developed a TrIP ecto-domain hIgG1 Fc fusion protein. This fusion protein has been used as an immunogen for the development of antibodies against TrIP in mice. This fusion protein has also been used to evaluate a possible ligand for TrIP.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
14 January 2019 |
| Date Type: |
Publication |
| Defense Date: |
13 November 2018 |
| Approval Date: |
14 January 2019 |
| Submission Date: |
18 December 2018 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
19 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
PI3K, Phosphatidylinositide-3-kinase, TCR signaling, PIK3IP1, TrIP, Transmembrane Inhibitor of PI3K, PI3K Interacting Protein 1, |
| Related URLs: |
|
| Date Deposited: |
14 Jan 2019 17:15 |
| Last Modified: |
14 Jan 2019 17:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/35869 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}